Pestiviruses cause economically important diseases in animals worldwide. The genus Pestivirus, within the family Flaviviridae, comprises three species: bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV), and border disease virus (BDV). The presence of a fourth separate group of pestiviruses comprising isolates from cattle and sheep has been recently described, and it is now generally accepted to refer to this additional species as BVDV-2; consequently, classical BVDV strains are named BVDV-1. See Becher et al., Virology 209(1):200-206 (1995).
BVDV-1 and BVDV-2 both cause acute infections in cattle (diarrhea, fever, hemorrhagic syndrome) as well as (if the infection occurs during pregnancy) abortion, malformation of the fetus and persistent infection of the calves. Persistently infected animals represent the major reservoir of the virus, and such animals may come down with the fatal mucosal disease (MD).
Classical swine fever virus (CSFV), formerly called hog cholera virus, is responsible for classical swine fever (CSF) or hog cholera (HC). Border disease virus (BDV) is typically found in sheep and causes border disease (BD). Symptoms similar to MD in cattle have also been shown to occur after intrauterine infection of lambs with BDV. For a review of pestiviruses, see Thiel et al., The pestiviruses., In Fields Virology, Fields et al. (eds.) (Lippincott-Raven, Philadelphia), pp.1059-1073 (1996).
Vaccines based on live or killed viruses, as well as of recombinant expression systems expressing viral proteins, have been developed for BVDV and CSFV and are presently used. The presently used live vaccines contain a more or less attenuated strain that replicates in the host. Attenuation may have been achieved by multiple passaging in homologous or heterologous cell culture (at suboptimal temperatures). However, these strains may still lead to transplacental infection and thereby cause fetal death, growth malformation, and persistent infection in the offspring.
A live vaccine strain with defined mutations resulting in a strong attenuation would avoid the disadvantages of the present generation of vaccines. Full-length infectious DNA copies have recently been constructed for BVDV (Meyers et al., J. of Virology 70:8606-8613 (1996)) and CSFV (Meyers et al., J. of Virology 70:1588-1595 (1996)). Their availability enables scientists to perform reverse genetic engineering in order to develop attenuated strains of BVDV or CSFV. However, it is still not known which region(s) of the genome should and can be modified to lead to a safe and effective vaccine strain.
Because of the importance of a safe and effective prophylaxis and treatment of pestivirus infections, there is a strong need for live and specifically attenuated vaccines with a high potential for induction of immunity as well as a defined basis of attenuation resulting in a significant reduction in the ability to replicate in the host.